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Received: 3 February 2017 Accepted: 4 May 2017 Published: xx xx xxxx
Brain-derived neurotrophic factor is regulated via MyD88/ NF-κB signaling in experimental Streptococcus pneumoniae meningitis Danfeng Xu1, Di Lian1, Zhijie Zhang1, Ying Liu2, Jiaming Sun3 & Ling Li1 Streptococcus pneumoniae meningitis is an intractable disease of the central nervous system (CNS). Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophic family and found to participate in the immune inflammatory response. In this study, we investigated if activation of the classical inflammatory signaling pathway, myeloid differentiation factor 88 (MyD88)/nuclear factorkappa B (NF-κB), regulates BDNF expression in experimental S. pneumoniae meningitis. MyD88 knockout (myd88−/−) mice and wild-type littermates were infected intracisternally with S. pneumoniae suspension. Twenty-four hours after inoculation, histopathology of brains was evaluated. Cytokine and chemokine in brains and spleens was analyzed using ELISA. NF-κB activation was evaluated using EMSA. Cortical and hippocampal BDNF was assessed using RT-PCR and ELISA, respectively. BDNF promoter activity was evaluated using ChIP-PCR. myd88−/− mice showed an obviously weakened inflammatory host response. This diminished inflammation was consistent with worse clinical parameters, neuron injury, and apoptosis. Deficiency in MyD88 was associated with decreased BDNF expression. Furthermore, we identified a valid κB-binding site in the BDNF promoter, consistent with activation of NF-κB induced by inflammation. To sum up, MyD88/NF-κB signaling has a crucial role in up-regulating BDNF, which might provide potential therapeutic targets for S. pneumoniae meningitis. Streptococcus pneumoniae meningitis is an invasive and often intractable disease of the central nervous system (CNS). Despite effective antibiotics and application of vaccinations, such infection is still associated with an unacceptably high morbidity and mortality1. The main limitation to advance in prevention and treatment of the disease is incomplete knowledge of its pathogenesis and pathophysiology. Generally, the host immune response, such as the activation of macrophages, production of cytokines and chemokines, and migration of leukocytes, is believed to be the first line of defense in response to bacterial invasion during the process of S. pneumoniae meningitis2. Toll-like receptors (TLRs), which are widely expressed in central resident macrophages, sense antigens from microorganisms, leading to the recruitment of myeloid differentiation factor 88 (MyD88) and the activation of downstream signaling pathways3, 4. MyD88 is crucial for the induction of a full innate inflammation response to most TLRs ligands, with the exception of TLR35. Furthermore, the MyD88-dependent pathway elicits nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) activation, which drives robust gene expression of cytokines and pro-inflammatory mediators6. However, increasing evidence has demonstrated that activation of NF-κB can lead to uncontrolled expression of those pro-inflammatory mediators, which contributes to the pathogenesis of disease processes7. Innate immune response is now widely recognized as a double-edged blade possessing both protective and damaging properties8. There is now solid evidence that intense inflammatory host response causes important damage to the brain, thus inducing unfavorable outcomes of meningitis9, 10. 1
Department of Pediatric Neurology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, P.R. China. 2Department of Clinical Laboratory, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, P.R. China. 3Department of Pathology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, P.R. China. Correspondence and requests for materials should be addressed to L.L. (email:
[email protected]) Scientific Reports | 7: 3545 | DOI:10.1038/s41598-017-03861-z
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Figure 1. Kaplan-Meier curves showing the survival rates of mice with PM. Survival rate of myd88−/− and wild-type mice following S. pneumoniae infection were 66.7% and 83.3%, respectively. KO: knockout, PM: pneumoniae meningitis, WT: wild-type.
Groups
Weight loss (g)
Clinical score Mortality rate
Infected myd88−/−
−2.83 ± 0.40a,b
3.33 ± 0.49a,b
33.30%
Control myd88−/−
−0.30 ± 0.30
0.00 ± 0.00
0
Infected wild-type
−2.03 ± 0.40c
2.42 ± 1.00c
16.70%
Control wild-type
−0.18 ± 0.27
0.00 ± 0.00
0
Table 1. Weight loss and clinical scores in different groups (mean ± SD). ap
